1. Field of the Invention
This invention relates to novel multibinding compounds that bind to Ca++ channels and modulate their activity. The compounds of this invention comprise 2–10 Ca++ channel ligands covalently connected by a linker or linkers, wherein the ligands in their monovalent (i.e. unlinked) state bind to and are capable of modulating the activity of one or more types of Ca++ channel. The manner of linking the ligands together is such that the multibinding agents thus formed demonstrate an increased biologic and/or therapeutic effect as compared to the same number of unlinked ligands made available for binding to the Ca++ channel. The invention also relates to methods of using such compounds and to methods of preparing them.
The compounds of this invention are particularly useful for treating diseases and conditions of mammals that are mediated by Ca++ channels. Accordingly, this invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and an effective amount of a compound of this invention.
2. State of the Art
Voltage-gated Ca++ channels mediate the influx of Ca++ into cells in response to changes in membrane potential. Because of their central roles in ion homeostasis and in cell signaling events, these channels are involved in a wide variety of physiological activities, e.g., muscle contraction, cardiovascular function, hormone and neurotransmitter secretion, and tissue growth and remodeling processes.
At least six types of calcium channels have been identified and characterized (Table 1, Appendix). The high-voltage activated Ca++ channels are formed by the heteromeric association of membrane proteins comprising at least three subunits α (α1, α2), δ, β (and γ in skeletal muscle). The α1 subunit alone is sufficient to form a functional channel, although the functional properties of the channel are subject to modification, particularly by the β subunit. The α1 subunit is organized into four homologous domains (I–IV), each domain including 6 transmembrane segments (S1–S6) (FIG. 1, Appendix). It is thought that the channel pore is formed from S5, S6 and the region between them, and that the voltage sensor resides in S4.
These channels exist in resting (closed), activated (open) or inactivated (desensitized) states. The resting channels open in response to depolarization of the membrane, then transition to an inactivated state. Repolarization is required for return to the resting state. As shown in Table 1, channels differ in their activation and inactivation properties.
Not surprisingly, Ca++ channels are recognized as important targets for drug therapy. They are implicated in a variety of pathologic conditions, including, e.g., essential hypertension, angina, congestive heart failure, arrythmias, migraine and pain.
Calcium channel antagonists are potent vasodilators and are widely used in the treatment of hypertension and angina pectoris. The compounds approved for clinical use in the U.S. fall into several chemical classes: the dihydropyridines (e.g., amlodipine, felodipine, nifedipine, nicardipine, isradipine, nimodipine); the benzothiazepines (e.g., diltiazem), phenylalkylamines (e.g., verapamil); and diarylaminopropylamine ether (e.g., bepridil).
The dihydropyridines, benzothiazepines and phenylalkylamines bind to distinct, but functionally coupled, sites on the α1 subunit of L-type channels at the interface of the IIIS6 and IVS6 transmembrane segments, such that the binding of any one class of drug can allosterically modulate the binding of drugs in the other two classes and the high affinity Ca++ binding site in the channel (see G H Hockerman et al, Annu. Rev. Pharmacol. Toxicol. 37: 361–96 (1997)). It has been suggested that more than one high affinity binding site may exist for dihydropyridines in voltage-dependent calcium channels (Kokubun et al, Molec. Pharmacol. 30: 571–584 (1986)). However, studies reported in the scientific literature cast doubt on this hypothesis. In particular, the antagonist activities of a series of 1,n-alkanediylbis(1,4-dihydropyridines) was reported to be essentially independent of the bridging carbon chain length, and similar to that of the monomeric drugs (Joslyn et al., J. Med. Chem. 31: 1489–1492 (1988)).
The clinical shortcomings of drugs in current usage are considerable. Various benzothiazepines and phenylalkylamines, for example, weaken cardiac contractility and are therefore contraindicated in patients with left ventricular dysfunction. Other Ca++ channel antagonists cause AV block, reflex tachycardia, excessive vasodilation and gastrointestinal problems. Their most common adverse side effects include headache, flushing, hypotension, nausea, dizziness, fatigue, edema, abdominal pain, constipation, and the like. With few exceptions, the currently used drugs have a short duration of action and must be administered frequently for sustained effects.
Thus, there continues to exist a need for novel compounds with greater tissue selectivity, increased efficacy, reduced side effects and a more favorable duration of action.